A variety of human diseases and conditions which are manifested by cardiac abnormalities or cardiac dysfunction can lead to heart failure. Heart failure is a pathophysiological condition in which the heart fails to pump blood at a rate commensurate with the requirements of the metabolizing tissues of the body. When the heart begins to fail, physiological mechanisms for modulating the function of the heart are utilized to increase heart rate and contractility.
The most important of the mechanisms that are responsible for modulating cardiac function are the adrenergic pathways. In a normal heart, these pathways are largely responsible for allowing cardiac pumping performance to meet the circulatory demands of increased activity by rapidly increasing or decreasing cardiac function according to circulatory demands. The cellular actions of these pathways are mediated through a family of receptors, called adrenergic receptors. There are two .beta.-adrenergic receptor subtypes, .beta..sub.1 and .beta..sub.2 which, when stimulated, initiate a G-protein coupled signaling cascade, resulting in immediate stimulation of pump performance. See FIG. 1.
When the heart begins to fail, adrenergic activity is stimulated by increased sympathetic nerve activity, presynaptic facilitation of norepinephrine release and eventually, decreased neuronal norepinephrine reuptake. Increased circulating epinephrine also stimulates cardiac .beta.-adrenergic receptors, particularly in the initial phase of heart failure.
In heart failure, the immediate stimulation of pump performance by .beta.-adrenergic mechanisms is subsequently aided by two additional means of stabilizing or increasing cardiac function. These are an increase in plasma volume, which in turn increases preload, and hypertrophy of the cardiac myocytes, which results in more contractile elements. The subcellular mechanisms mediating these additional cardiac functions include both the .beta.-adrenergic receptor pathways and the .alpha..sub.1 -adrenergic receptor pathway, among other myocellular pathways.
In the failing ventricular myocardium, the exposure to elevated levels of cognate agonists causes the adrenergic receptors to undergo regulatory changes. In particular, the .beta..sub.1 -adrenergic receptor exhibits down-regulation or loss of receptor protein and may also be partially uncoupled from the signaling response. .beta..sub.2 -adrenergic receptors are not down-regulated, but are weakly uncoupled from the signaling response. The .alpha..sub.1 -adrenergic receptors are slightly up-regulated and are partially uncoupled from the signaling response. These changes in adrenergic receptor expression and signaling partially withdraw the cardiac myocyte from chronic stimulation, although some adrenergic function remains. The increased agonist exposure, however, continues to chronically stimulate the remaining adrenergic signaling function, resulting in the compromise of the modulatory effects of the adrenergic system. Therefore, the prime functional capabilities of the adrenergic system, to rapidly and substantially increase or decrease cardiac function according to demand, are compromised, while the adverse effects of chronic stimulation of cardiac function remain.
Numerous compounds have been identified and used to inhibit the functions of the .beta.-adrenergic receptors, and thus, eliminate the adverse effects of chronic myocardial stimulation through the adrenergic pathways. These compounds, often called .beta.-adrenergic receptor antagonists, .beta.-adrenergic antagonists or .beta.-blockers, interact with the .beta.-adrenergic receptors and thereby inhibit or prevent cellular signaling by the endogenous agonists. One .beta.-adrenergic antagonist can differ from another in a variety of ways, including by receptor subtype specificity, effect on expression of the adrenergic receptor, and effect on adrenergic receptor signaling.
Although .beta.-adrenergic antagonists are important therapeutic tools for use in patients experiencing heart failure, these drugs often cause adverse side effects, such as bradycardia, myocardial depression, dyspnea, easy fatigability, fluid retention and worsening of heart failure. The characteristics which contribute to the undesirable side effects of .beta.-adrenergic antagonists are controversial and not well understood. See Kelly and Smith, in Heart Disease: A Textbook Of Cardiovascular Medicine, Chapter 16 at page 488 (5th ed., Braunwald ed., 1997).
Another therapy for heart failure that has been investigated is the use of positive inotropic agents. Positive inotropic agents strengthen heart muscle contractility, and they exert their effects through the second messengers of the signal transduction pathways involved in modulating contractile function (illustrated in FIG. 1). Table 1 lists the second messengers involved in mediating a positive inotropic response for various inotropic agents. As shown in Table 1, positive inotropic agents use only a limited number of second messengers to mediate their cellular effects, and some use more than one second messenger. Table 2 lists the three most commonly observed second messengers and their effects on important processes in the heart and vascular smooth muscle, including increases in the heart rate, contractility and vasodilation. As seen in Table 2, only the intracellular second messenger cyclic adenosine monophosphate (cAMP) is capable of producing vasodilation and a positive inotropic effect. Cyclic AMP also produces an increase in heart rate, a very counterproductive property for a heart failure medication. In addition, all positively inotropic second messengers carry an arrhythmogenic risk that is usually dose-related.
TABLE 1 ______________________________________ Second messengers used by various classes of inotropic agents Class Second messengers ______________________________________ .beta.-adrenergic receptor Cyclic AMP, Ca.sup.2+ agonists (G.sub.s .fwdarw. Ca.sup.2+ channel) Ca.sup.2+ channel agonists Ca.sup.2+ .alpha..sub.1 -adrenergic receptor Inositol triphosphate/DAG agonists Phosphodiesterase Cyclic AMP inhibitors Quinolones Cyclic AMP, ?Ca.sup.2+ Calcium sensitizers Ca.sup.2+, cyclic AMP Cardiac glycosides Ca.sup.2+ Na.sup.+ -channel agonists Ca.sup.2+ ______________________________________ G.sub.s, stimulatory G protein; DAG, diacylglycerol; AMP, adenosine monophosphate.
TABLE 2 ______________________________________ Effect of second messengers on cardiovascular responses Second Heart Cardiac Vascular messenger rate contraction response ______________________________________ Cyclic AMP .uparw..uparw. .uparw..uparw..uparw. .uparw..uparw..uparw. Dilation IP.sub.3 /DAG .rarw..fwdarw. .uparw. .uparw..uparw. Constriction Ca.sup.2+ .rarw..fwdarw. .uparw..uparw. .uparw. Constriction ______________________________________ IP.sub.3, inositol triphosphate.
In the late 1970s and early 1980s the high degree of acceptance of the potential of positive inotropic agents by cardiologists and physicians was based on the intuitive belief that pharmacologic reversal of the intrinsic defects in myocardial contractility that characterize the failing heart could `cure` the heart failure process. Since myocardial failure is characterized by a downward/rightward shift in the length-tension relationship, and positive inotropic agents shift this relationship upwards and to the left [Katz, J. Am. Coll. Cardiol., 1, 42-51 (1983)], it seemed logical that this form of therapy would help the failing heart. Unfortunately, the concept was disproved by the xamoterol and Prospective Randomized Milrinone Survival Evaluation (PROMISE) trials which, respectively, demonstrated that a .beta.-adrenergic receptor partial agonist (xamoterol) and a phosphodiesterase inhibitor (milrinone) increased mortality in subjects with heart failure. The Xamoterol in Severe Heart Failure Study Group, Lancet, 336, 1-6 (1990); Packer et al. for the PROMISE Study Group, N. Engl. J. Med., 325, 1468-1475 (1991). The PROMISE trial ended the simple paradigm that positive inotropic therapy was the answer for ambulatory heart failure. In particular, influential opinion leaders in the heart failure field argued convincingly that any agent acting through a positive inotropic mechanism is likely to adversely affect the natural history of heart failure. Packer, Lancet, 340, 92-95 (1992).
In advanced, late-stage heart failure, .beta.-adrenergic antagonists cannot be used, and often the only therapy available is intravenous positive inotropic agents. Although patients receiving intravenous inotropic agents usually feel better and improve hemodynamically for a short time, this treatment is expensive and has the potential to increase mortality. Other uses of positive inotropic therapy, including oral forms of positive inotropes, have been abandoned because of the above-mentioned increase in mortality.
It has been suggested that many of the adverse effects of positive inotropic agents could theoretically be ameliorated by simultaneous treatment with antagonists of neurohormonal activation such as an angiotensin converting enzyme (ACE) inhibitor or a .beta.-adrenergic antagonist. Bristow and Lowes, Coronary Artery Disease, 5, 112-118 (1994). Actual results with ACE inhibitors have been mixed. Id. Two small, uncontrolled studies provide preliminary support for the use of a positive inotropic agent and a .beta.-adrenergic receptor antagonist. Galie et al., Cardiovasc. Drugs Ther., 7, 337-347 (1993); Gilbert et al., Clin Res., 40, 259A (1992). However, the results of these studies are limited to the specific conditions used in the studies and cannot be extrapolated. Galie et al., Cardiovasc. Drugs Ther., Vol. 7, pp. 307-347 (1993). Also, larger, controlled studies are needed before this therapy can be considered useful. Bristow and Lowes, Coronary Artery Disease, 5, 112-118 (1994).
Chronic heart failure is a progressive disease syndrome which is associated with high degrees of morbidity and mortality despite medical therapy. Although heart transplantation can improve outcomes, a limited organ donor supply confines this treatment to fewer than 5% of subjects who could benefit from it. The effects of medical therapy on chronic heart failure are largely confined to modest effects (15-20% reductions in mortality) observed with ACE inhibitors in subjects with mild or moderate heart failure. Clearly, there exists a need for more effective pharmaceutical treatments for heart failure, especially for advanced, late-stage heart failure.